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Zinc metabolism in rheumatoid arthritis: plasma and urinary zinc and relationship to disease activity.

OBJECTIVE: To study zinc absorption in patients with active rheumatoid arthritis (RA). METHODS: We studied zinc tolerance tests and 24 hour urinary zinc excretion before and after ingestion of 50 mg elemental zinc in 8 healthy volunteers (Group 1) and 13 patients with low RA activity (Group 2) and 16 patients with high RA activity (Group 3). RESULTS: In Group 1, plasma zinc rose from 111 +/- 7 micrograms/dl to a peak of 200 +/- 24 micrograms/dl (mean +/- SEM) in 2 h. In Groups 2 and 3, plasma zinc before zinc ingestion was significantly lower than that of the control group (p < 0.00001 for both groups) and showed no significant increase in plasma after ingestion. Twenty-four hour urinary zinc excretions before and after zinc ingestion were significantly lower (p < 0.01, p < 0.0001 for Group 2; p < 0.05, p < 0.01 for Group 3, respectively) than those in the control group. CONCLUSION: These results are compatible with zinc malabsorption and consequent zinc deficiency in patients with RA. Whether zinc deficiency contributes to perpetuation of disease activity by compromising cellular immune function needs further investigation.

Adult↗

A novel zinc compound (zinc monocysteine) enhances the antioxidant capacity of human retinal pigment epithelial cells.

PURPOSE: The aim of this study was to document the effect of a novel zinc amino acid combination on the concentrations of important antioxidants in cultured human retinal pigment epithelial (hRPE) cells. METHODS: Primary confluent hRPE cells were treated with 30 microM of zinc acetate, zinc chloride, zinc cysteine, and zinc sulfate. The antioxidants catalase, glutathione, glutathione peroxidase, and metallothionein were measured. MTT assays were performed to determine the relative protection of the zinc compounds from the cytotoxic effects of H202 and t-butyl hydroperoxide. RESULTS: Catalase and glutathione peroxidase activities were increased by the zinc formulations compared with the untreated control. Glutathione and metallothionein content were also increased. The greatest increases occurred with zinc conjugated to the amino acid cysteine. The MTT assays showed that zinc monocysteine protected cultured RPE cells from the toxicity of H2O2 and t-butyl hydroperoxide. CONCLUSIONS: Our results demonstrate that zinc treatment of RPE cells increases antioxidants and protects cultured RPE cells from the cytotoxic effects of H2O2 and t-butyl hydroperoxide. The results show that zinc conjugated to cysteine offers greater benefits than either zinc salts or cysteine alone.

Antioxidants↗

Effect of proteins on availability of zinc. I. Gastrointestinal transit time of casein and whey protein and zinc absorption in weaned rats.

The availability of zinc from isolated casein (CasD) was compared with that from whey protein (WpD) in 23-25 day old rats. The study was designed to show the course of the gastrointestinal transit time of either chyme (radiolabeled by 141Ce as a non-absorbable marker) or zinc (as 65Zn) in groups of 9 to 12 animals each. Animals were killed either 1/4, 1/2, 1, 2, 6, 12 or 24 hours after intragastric intubation of the protein suspensions. Immediately afterwards, intragastric pH was measured and the determination of zinc retention in intestinal tissues and liver as well as in the carcass was performed. 30 and 60 minutes after intubation the intragastric pH of the CasD group was significantly lower than that of the WpD group. The precipitation behaviour of the two protein fractions - compact curd formation by the CasD versus flocculent structure of the WpD - was determining for the pattern of gastric emptying. With the WpD the chyme was emptied according to an exponential function; while the CasD precipitate left the stomach in three distinct phases. With either protein suspension zinc left the stomach ealier than the bulk of the chyme, indicating a partial disintegration of the zinc-protein-complexes. With the WpD, zinc was emptied exponentially, whereas with the CasD a biphasic emptying pattern was found. Ileum was found to be the main zinc absorbing segment, mainly due to the long time of contact with zinc. After 2 and 12 hours zinc retention from the CasD was significantly higher than that from the WpD, however, after 24 hours retention was significantly better from the WpD. From the present study it can be concluded that, for comparison of zinc availability from diets containing different proteins, short-term experiments are not appropriate. Furthermore, it can be supposed that preabsorptive processes in the stomach are crucial for the availability of zinc.

Animals↗

Mild to moderate zinc deficiency in short children: effect of zinc supplementation on linear growth velocity.

Twenty-one prepubertal, short Japanese children (11 boys) without endocrine abnormalities were identified as having mild-to-moderate zinc deficiency by zinc kinetics studies (zinc body clearance > or = 20 ml/kg per hour). Only one child had a serum zinc level < 65 micrograms/dl (cutoff level). A total of 10 children (5 boys) received 5 mg/kg per day of zinc sulfate for 6 months; 11 untreated children (6 boys) served as control subjects. During treatment, calorie intake (p < 0.01), growth velocity (p < 0.01), serum zinc, calcium, and phosphorus concentrations, alkaline phosphatase activity (p < 0.001), percentage of tubular reabsorption of phosphorus (p < 0.05), ratio of maximal tubular reabsorption rate for phosphorus to the glomerular filtration rate (p < 0.05), serum osteocalcin level (p < 0.01), and plasma insulin-like growth factor 1 (p < 0.05) were significantly increased, but urinary excretion of growth hormone was unchanged in the zinc-supplemented group. All these values were unchanged in the untreated children. We conclude that zinc supplementation is effective for inducing growth in short children with zinc deficiency, and that body zinc clearance tests facilitate detection of marginal zinc deficiency.

Administration, Oral↗

Zinc release from the CH2C6 zinc finger domain of FILAMENTOUS FLOWER protein from Arabidopsis thaliana induces self-assembly.

The FILAMENTOUS FLOWER gene from Arabidopsis thaliana is a member of a gene family whose role is to specify abaxial cell fate in lateral organs. Analysis of the amino-terminal region of the FILAMENTOUS FLOWER protein suggests that seven cysteine residues at positions 14, 26, 30, 33, 54, 56, and 57, and two histidine residues at positions 18 and 24 contribute to a putative zinc finger motif, Cys-X(3)-His-X(5)-His-X-Cys-X(3)-Cys-X(2)-Cys-X(20)-Cys-X-Cys-Cys. Zinc determination experiments revealed that the FILAMENTOUS FLOWER protein binds two zinc ions per molecule. Chemical modification was required to release one zinc ion, whereas the other was released spontaneously or more rapidly in the presence of metallochromic indicator. The loss of a zinc ion and the subsequent structural change of the zinc finger domain were correlated with the multimerization of the FILAMENTOUS FLOWER protein. A cysteine residue at position 56 in the FILAMENTOUS FLOWER protein potentially interferes with zinc ligation within the zinc finger and causes this zinc release. In support of this, substitution of the Cys(56) by alanine suppressed both the zinc release and the multimerization of the FILAMENTOUS FLOWER protein. Deletion analysis showed that the region between positions 45 and 107 functions in the intermolecular contacts between FILAMENTOUS FLOWER proteins. This region corresponds to the carboxyl-terminal half of the zinc finger domain and the following hydrophobic region containing two putative alpha-helices. Our results suggest that the FILAMENTOUS FLOWER protein forms a range of different conformers. This attribute may lead to a greater degree of functional flexibility that is central to its role as an abaxial cell fate regulator.

Alanine↗

Effect of dietary zinc sources and pregnancy on zinc utilization in adult women fed controlled diets.

Five nonpregnant and 10 pregnant women participated in 21-day confined metabolic studies. Two diets each providing 16 mg of zinc per day were fed. In one diet 70% of the total zinc was provided by animal products and 30% was contributed by plant sources. In the second diet the proportions were reversed. Apparent absorption of zinc was determined using the balance technique. During the last 15 days of the study, zinc intake was only slightly greater than the amount of zinc excreted in feces. Mean apparent absorption values did not exceed 5% and did not vary due to diet or pregnancy. Zinc bioavailability was also assessed by measuring the apparent absorption of a stable isotope of zinc (70Zn) added to the diet. There was no significant effect of either diet or pregnancy on 70Zn absorption, which averaged about 25%. Serum zinc values were normal throughout the study and did not change significantly as a function of diet. The pregnant women, however, maintained values that were 19-27% lower than those of the nonpregnant women. In summary, the substitution of animal sources of zinc by plant products did not reduce zinc bioavailability or alter zinc utilization.

Adult↗

Comparison of the effect of beta-alanyl-L-histidinato zinc and its zinc-chelating ligand on bone metabolism in tissue culture.

The present investigation was undertaken to compare the effects of beta-alanyl-L-histidinato zinc (AHZ) and its zinc-chelating ligands on bone metabolism in tissue culture. Calvaria were removed from 3-week-old male rats and cultured for up to 72 h in Dulbecco's modified eagle medium containing zinc sulfate, AHZ, di(N-acetyl-beta-alanyl-L-histidinato)zinc (AAHZ), and di(histidino)zinc (HZ). The bone calcium content and alkaline phosphatase activity were significantly increased in the presence of AHZ or AAHZ (10(-8)-10(-5) M). Those increases were seen at 10(-7) to 10(-5) M zinc sulfate and HZ. The bone deoxyribonucleic acid (DNA) content was significantly increased by AHZ or AAHZ with 10(-7) to 10(-5) M, while 10(-7) M zinc sulfate and HZ had no effect. Thus, AHZ and AAHZ had more potent effect than that of zinc sulfate and HZ. The effect of AHZ, AAHZ and HZ (10(-5) M) increasing bone alkaline phosphatase activity was abolished by the presence of 10(-4) M dipicolinate, a chelator of zinc. Moreover, the effect of these zinc compounds on bone metabolic indices was not seen in the presence of 10(-6) M cycloheximide. The present results suggest that the effect of AHZ and AAHZ on bone metabolism is more potent than that of zinc sulfate and HZ.

Alkaline Phosphatase↗

Performance and carcass quality of steers supplemented with zinc oxide or zinc methionine.

Forty-five Angus steers (avg initial wt 330 kg) were individually fed for 112 d to assess the value of supplemental Zn and source on performance and carcass quality. Steers had ad libitum access to a control diet (81 ppm Zn) of 33% whole corn, 33% ground milo, 15% cottonseed hulls and 13% cottonseed meal, or this control diet with 360 mg Zn/d added from either zinc methionine or zinc oxide. Steers were slaughtered on d 114, and carcass composition was determined by specific gravity. Average daily gain and feed efficiency were not affected by dietary treatments. Steers fed zinc methionine had a higher (P less than .05) USDA quality grade than those fed the control and zinc oxide diets. Marbling score was higher (P less than .05) for steers fed zinc methionine than for those fed control and zinc oxide treatments (4.4 vs 4.0 and 4.0, respectively, where 3 = slight, 4 = small, 5 = modest). Steers fed zinc methionine tended to have more (P less than .10) external fat (13 mm) than steers fed the control diet (10 mm); steers supplemented with zinc oxide had intermediate amounts of external fat (11 mm). Steers fed zinc methionine had 10.5 and 12.8% more (P less than .05) kidney, pelvic and heart (KPH) fat than steers fed control or zinc oxide diets, respectively. The effects of zinc methionine on carcass quality grade and marbling score may be due to Zn and (or) methionine. Regardless of the mechanism, the difference represents a potential economic benefit to producers.

Animals↗

Divergent consequences arise from metallothionein overexpression in astrocytes: zinc buffering and oxidant-induced zinc release.

Excessive accumulation of the heavy metal zinc is cytotoxic. As a consequence, cellular vulnerability to zinc-induced injury may be regulated by the abundance of proteins that maintain intracellular free zinc concentrations ([Zn2+]i). In this study, we overexpressed the zinc-binding protein metallothionein-II (MT) in astrocytes to assess its impact as (1) an acute zinc buffering mechanism, and (2) an oxidant-releasable zinc pool. Overexpression of MT in primary astrocyte cultures was accomplished using an adenoviral vector. Using the zinc-sensitive fluorescent indicator mag-fura-2, we monitored [Zn2+]i after stimulating zinc influx or oxidant treatment. With MT overexpression, we observed an acute buffering effect manifested as a dampening of stimulus-induced increases in [Zn2+]i. In contrast, we also saw enhanced zinc release with application of the sulfhydryl oxidizing agent 2,2'-dithiodipyridine. These results indicate that overexpression of a zinc-binding protein can quickly diminish [Zn2+]i following zinc influx, but elevate [Zn2+]i under conditions of oxidative stress, providing protective yet potentially endangering effects.

Animals↗

Role of zinc in regulation of protein tyrosine phosphatase activity in osteoblastic MC3T3-E1 cells: zinc modulation of insulin-like growth factor-I's effect.

Zinc, an essential trace element, has been demonstrated to stimulate bone growth in animal and human. The cellular mechanism by which zinc stimulates bone growth has not been fully clarified. The effect of hormone and zinc on protein tyrosine phosphatase activity in osteoblastic MC3T3-E1 cells was investigated. Cells were cultured for 72 h in medium containing 10% fetal bovine serum (FBS) to obtain subconfluent monolayers, and then exchanged to culture medium containing either vehicle, zinc sulfate or various hormones in the absence of 10% FBS. After medium change, cells were cultured for 48 h. Protein tyrosine phosphatase activity in the lysate of cells was significantly increased by culture with zinc (10(-6) - 10(-4) M). The effect of zinc in increasing the enzyme activity was completely blocked by culture with cycloheximide (10(-7 )M), an inhibitor of protein synthesis, or 5, 6-dichloro-l-beta-D- riboifuranosylbenzimidarzole (DRB) (10(-6) M), an inhibitor of translational activity. Addition of calcium chloride (10 microM) into the reaction mixture caused a significant increase in protein tyrosine phosphatase activity; this increase was completely blocked in the presence of trifluoperazine (50 microM), an antagonist of calmodulin. Culture with zinc caused a significant increase in Ca2+/calmodulin-dependent protein tyrosine phosphatase activity in osteoblastic cells. Protein tyrosine phosphatase activity was significantly raised by culture with parathyroid hormone (human PTH [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33]; 10(-7) M), 17beta-estradiol (10(-7) M), insulin-like growth factor-I (IGF-I; 10(-8) M) or insulin (10(-8) M). The enzyme activity was not significantly enhanced by the addition of calcium (10 microM) into the reaction mixture. The effect of PTH or IGF-I in increasing protein tyrosine phosphatase activity was completely blocked by culture with DRB. The IGF-I-induced increase in enzyme activity was significantly enhanced by culture with zinc. Such an effect was not seen in the case of PTH. Moreover, the effect of IGF-I in increasing proliferation of osteoblastic cells was significantly enhanced by culture with zinc. The effect of PTH was not enhanced by zinc. This study demonstrates that protein tyrosine phosphatase activity in osteoblastic cells is enhanced by various bone anabolic factors, and that zinc modulates the effect of IGF-I on protein tyrosine phosphatase activity and cell proliferation.

3T3 Cells↗

Serum zinc levels and urinary zinc excretion in patients with bronchogenic carcinoma. Effects of tumor resection.

Low serum zinc levels and high urinary zinc excretion were found in 25 patients with bronchogenic carcinoma. Twenty of them underwent successful removal of the tumor by lobectomy or pneumonectomy; in the other 5 patients surgical exploration revealed unresectable pulmonary lesions. The latter had significantly lower serum zinc and higher urinary zinc levels than the patients in whom surgical removal of the tumor could be performed. Tumor resection was followed by restoration of serum and urinary zinc to normal. In contrast, in the inoperable patients a further decrease in serum zinc and no significant change in urinary zinc excretion were noted 15 days after thoracic exploration. In both patient groups a significant negative correlation existed between preoperatively obtained values of serum and urinary zinc. Hypozincemia in patients with bronchogenic carcinoma may result from an increase in urinary zinc losses, probably related to a decrease in zinc binding to plasma proteins. Determination of serum and urinary zinc may be useful in evaluating the prognosis of primary lung cancer.

Adenocarcinoma↗

Low-molecular-weight zinc-binding ligand: a regulatory modulator for intestinal zinc transport.

1. In the last two decades, vast numbers of studies on the zinc nutriture of animals and man have been made. However, the biochemical and physiological events in controlling zinc nutrition are still poorly understood. This report concerns the progress made toward understanding the intestinal zinc absorption and secretion mechanisms. 2. Evidence is accumulating that zinc absorption is a facilitated diffusion while zinc secretion is an active transport. 3. It is known that a low molecular weight zinc-binding ligand (LMW-ZBL) is a key regulator of intestinal zinc absorption, possibly a carrier molecule across the intestinal mucosal cells. Some high molecular weight zinc-binding ligands also appear to be involved in regulating intestinal zinc transport. 4. The identity of the LMW-ZBL is a matter of controversy and its specific role in regulating intestinal zinc transport is not well defined. 5. According to the available literature, no systemic investigations have been made to elucidate the intestinal zinc transport mechanisms, and much more information is needed to fully understand them.

Animals↗

Urinary zinc excretion in a patient with burns: a caveat when using bladder catheters in urine zinc studies.

The results of a longitudinal study on plasma and urine zinc concentrations in a patient with 68 per cent burns are described. Special attention was paid to possible zinc contamination due to the use of bladder catheters for urine sampling. The course of the plasma and urine zinc concentrations during the first 50 days in hospital was comparable to those reported in the literature. It was shown that surgery was associated with a pronounced rise in urine zinc level, while catheter replacement caused no significant increase in urinary zinc content in this particular patient. However, measurements of zinc content of and zinc release from three types of bladder catheters showed that the two types of latex-based catheters contained about 0.25 per cent zinc, versus 0.01 per cent in the siliconelastomer equivalent. During an 8 h perfusion latex catheters released about 1.2 mumols zinc (2.5 mumols/l). Possible errors in urine zinc determinations due to zinc contamination from catheters are calculated. Recommendations are made for minimizing these errors.

Adult↗

Tetanically released zinc inhibits hippocampal mossy fiber calcium, zinc and synaptic responses.

At the zinc-enriched mossy fiber synapses from hippocampal CA3 area, electrical or chemical stimulation evokes zinc release from glutamatergic synaptic vesicles that may cause different pre- or postsynaptic actions. Besides zinc that can be co-localized with glutamate and GABA, the mossy fibers contain a very high density of ATP-sensitive potassium channels that are activated by zinc. We have investigated the possibility that intensely released zinc inhibits presynaptic calcium changes and consequently zinc and glutamate release. The studies were made combining optical recording of fast presynaptic calcium and zinc signals, using the fluorescent indicators Fura-2 and N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide, respectively, with measurements of field potentials. We have observed that strong tetanic stimulation caused posttetanic depressions of electrically induced presynaptic calcium and zinc signals and of synaptic responses, the depressions being blocked by zinc chelators. These results suggest that endogenously released zinc has an inhibitory role, mediated by presynaptic ATP-sensitive potassium channels and/or presynaptic calcium channels, that leads to the depression of zinc and glutamate release.

Adenosine Triphosphate↗

Zinc transporters in the mouse placenta show a coordinated regulatory response to changes in dietary zinc intake.

The aim of the study was to determine if the expression of zinc transporters in the mouse placenta is regulated by dietary zinc, commensurate with regulating the supply of zinc to the fetus. Mice were fed diets differing only in the concentration of zinc (moderately zinc-restricted (ZnR)--15 mg Zn/kg; zinc-adequate (ZnA)--50 mg Zn/kg; zinc-supplemented (ZnS)--150 mg Zn/kg) from the onset of pregnancy until collection of tissue at day 17. Compared with mice fed the other diets, fetal weight was reduced in the ZnR group and total non-embryonic weight gain was reduced in mice fed the ZnS diet. Transcript levels of metallothionein and the zinc transporters ZnT1, ZnT4 and ZIP1 were reduced in the placenta of mice fed both the ZnR and ZnS diets compared with mice fed the ZnA diet. Placental ZnT7 and fetal liver metallothionein transcript levels did not differ significantly between mice fed the three diets and placental ZnT5 was reduced in mice fed the ZnS compared with the ZnA diet but did not differ significantly between the ZnA and ZnR diets. The pattern of mRNA expression in placenta was reflected at the protein level for ZnT1. Levels of ZnT5 protein were also highest in mice fed the ZnA diet. Both ZnT1 and ZnT5 were detected in the human villous syncytiotrophoblast by immunohistochemistry. The data indicate that the expression of zinc transporters in mouse placenta is responsive to dietary zinc supply but this modulation of expression is insufficient to maintain optimum fetal nutrition at even a modest level of dietary zinc restriction.

Animals↗

Zinc intake and plasma zinc level are maintained in men consuming cholesterol-lowering diets.

OBJECTIVE: Reduced zinc intake has been reported when cholesterol-lowering diets are adopted. This study examined whether such diets compromise the zinc status of men with hypercholesterolemia. DESIGN: Zinc intake on baseline 4-day food records and baseline plasma zinc levels were compared with intake and levels 12 and 24 months after subjects adopted a low-fat, increased-fiber diet. Dietary fiber intake, supplement use, alcohol intake, and exercise were evaluated as possible confounding variables. SUBJECTS: Subjects were free-living men (n = 365) with baseline cholesterol level above the 75th percentile who were participants in a randomized trial comparing cholesterol-lowering diets with goals of 30%, 26%, 22%, and 18% of energy from fat and 300, 200, 100, and 100 mg cholesterol, respectively. STATISTICAL ANALYSES: Data were analyzed using two sample t tests, multiple linear regression, and analysis of variance. RESULTS: For all subjects combined, mean fat and cholesterol intakes approached or met the guidelines of the National Cholesterol Education Program step 2 diet, with approximately 30 g fiber per day. Density (mg/1,000 kcal) of zinc intake was unchanged from the baseline value. We found a slightly positive relationship between fiber and zinc intakes; no relationship between fiber intake and plasma zinc level; no effect of supplement use (category included all types of supplements), alcohol use, or level of exercise on plasma zinc levels; and no difference by dietary assignment in zinc intake or plasma zinc levels. APPLICATION: Zinc status does not appear to be at risk in adult men who adopt cholesterol-lowering diets. These results may not be generalized to higher-risk population groups or situations in which dietary counseling is less comprehensive.

Adult↗

Role of cellular zinc in programmed cell death: temporal relationship between zinc depletion, activation of caspases, and cleavage of Sp family transcription factors.

Zinc is a potent inhibitor of apoptosis, whereas zinc depletion induces apoptosis in many cell lines. To investigate the mechanisms of zinc depletion-induced apoptosis, HeLa cells were treated with the membrane permeable metal ion chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). TPEN decreased the intracellular level of zinc and induced apoptosis with a characteristic cellular pattern, i.e. cell shrinkage and formation of apoptotic bodies, with DNA fragmentation and formation of a typical DNA ladder pattern. Following TPEN treatment, caspases-3, -8, and -9 were activated and caspase target proteins, poly(ADP-ribose) polymerase, and Sp transcription factors were cleaved. These effects were inhibited by adding zinc to the medium. To assess the role of zinc in the activation of the caspase cascade, we compared zinc inhibition during tumor necrosis factor alpha/cycloheximide- and etoposide-induced apoptosis with that induced by TPEN. Zinc addition partially inhibited caspase-3 activation, but not caspase-8 and -9 cleavage in HeLa cells treated with tumor necrosis factor alpha or etoposide. These results suggest that caspase-3 is rapidly and directly activated by zinc chelation, without a requirement for an upstream event. Caspase-3 activation is therefore the main event leading to apoptosis after intracellular zinc chelation. Finally, we conclude that cellular zinc inhibits apoptosis by maintaining caspase-3 inactive.

Analysis of Variance↗

Relationship between brain zinc and transient learning impairment of adult rats fed zinc-deficient diet.

The relationship between brain zinc and learning behavior was studied based on the data of 65Zn localization in the hippocampal formation. Learning behavior, tested by passive avoidance performance, of 6-week-old rats improved significantly compared to that of 4-week-old rats and it was maintained at 20 weeks of age. When 8-week-old rats were fed zinc-deficient diet for 4 weeks, the learning behavior was significantly impaired. However, it was recovered to almost normal level by feeding with control (zinc-adequate) diet for 5 weeks. These results demonstrate that a proper zinc supply to the brain is necessary for improvement and maintenance of learning ability. Although an appreciable decrease in brain zinc was not observed in the rats fed zinc-deficient diet for 4 weeks, significant decrease of hippocampal zinc was observed in rats fed zinc-deficient diet for 12 weeks. Moreover, synaptosomal zinc in the hippocampal formation and cerebral cortex was significantly decreased by the 12 weeks of zinc deprivation. These results suggest that the decrease of vesicular zinc in the hippocampal formation and cerebral cortex is involved in the transient learning impairment of adults rats.

Age Factors↗